Geneseroline derivatives of the above formula (I), having anticholinesterase activity, are disclosed in the European patent 0599890, in the name of Chiesi. These compounds can be used in the treatment of disorders of central nervous system.
The examples of preparation of the compounds of formula (I), as disclosed in the above patent, comprise the following steps:
a) hydrolysis of eserine to eseroline; ##STR3## PA1 b) O-acylation of eseroline with reagents capable of introducing the desired function --CO--NHR, wherein R is as above defined; PA1 c) oxidation of the so obtained eseroline aminocarbonyl derivatives to give the corresponding aminocarbonyl derivatives of geneseroline. PA1 a) oxidation of eserine with hydrogen peroxide in the presence of a base and subsequent hydrolysis to geneseroline, without isolating the intermediate geneserine; PA1 b) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined in the above formula (I), in the presence of a basic catalyst; PA1 c) optional transformation into a pharmaceutically acceptable salt. PA1 a) oxidation of a compound of formula (II) with peracids or peroxides, preferably hydrogen peroxide, in an alcoholic solvent or in a water-alcohol mixture to give a compound of formula (III); ##STR7## PA1 b) hydrolysis of the compound of formula (III) to geneseroline with a mineral acid or an organic acid, which does not reduce the N-oxide group; PA1 c) acylation of geneseroline with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above and in the same reaction conditions disclosed for the process outlined in scheme 1 above; PA1 d) optional transformation into a pharmaceutically acceptable salt. PA1 a) hydrolysis with a mineral or an organic acid of a compound of formula (II) ##STR9## PA1 wherein R.sub.1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions, such as for example ethyl, tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl; to give eseroline (IIa) ##STR10## PA1 b) acylation of eseroline (IIa) with an isocyanate of formula R--N.dbd.C.dbd.O, wherein R is as defined above and in the same reaction conditions disclosed for the process outlined in scheme 1 above; PA1 c) oxidation of the so obtained eseroline aminocarbonyl derivative to the corresponding geneseroline aminocarbonyl derivative; PA1 d) optional transformation into a pharmaceutically acceptable salt.
More specifically, in the examples of the patent, the preparation of only n-heptylaminocarbonylgeneseroline is disclosed.
Substituted imidazolureas or isocyanates are used for the acylation reaction.
Oxidation of eseroline derivatives to the corresponding geneseroline derivatives is carried out by using peracids or organic peroxides, such as m-chloroperbenzoic, monoperphthalic, peracetic acid, hydrogen peroxide, in inert solvents, such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide.
Alternatively, the compounds of formula (I) have been prepared starting from geneseroline through hydrolysis of the methylaminocarbonyloxy group, and subsequent acylation, carried out by always using N-alkylimidazoleurea. Geneseroline is a well-known compound (Yu Q.S. et al. Journal of Natural Products, 52(2), 332-336, 1989).
The processes therein disclosed are unsuited to industrial scale, because of problems related to the cost of the starting alkaloid, reaction speed, yield and purity of the final product, due to side reactions.
It has now been found, and it is an object of the present invention, a process for the preparation of the compounds of formula (I), which is simple, economical, safe and applicable on industrial scale with good quantitative yields.